Structural imaging of morphological or anatomical features of the retina of an eye of a patient can reveal information regarding the state of the eye and even a prognosis for disease. Some of the features can be due to pathologies such as diabetic retinopathy (DR), aged-related macular degeneration (AMD), a detachment of the retinal pigment epithelium from its basement membrane (PED), accumulations of lipids (exudates; drusen), and poorly phagocytized photoreceptor outer segments. Alternative imaging methods, deriving more dynamic or functional information can also be used to identify problem areas. The information obtained from functional imaging can augment and/or supplement that of structural imaging information.
Diabetic retinopathy is one of the major causes of legal blindness in the industrially developed world. The most common vision threatening complication of diabetic retinopathy is diabetic maculopathy incorporating diabetic macular edema and macular ischemia (microangiopathy), caused by hyperglycemic-initiated cellular changes. A structural hallmark of diabetic retinopathy or of diabetic maculopathy is in the appearance of vascular changes such as microaneurysms and capillary occlusions. Commonplace responses to DR such as laser surgery usually only begin when severe damage has occurred to the retinal structure detected by an optical imaging system, or when the patient is experiencing a functional vision deficit.
Often structural information of the retina is obtained using a variety of optical techniques to aid in diagnosing the existence and progression of the disease. Structural information or metrics can be the thicknesses of various retinal layers; or can be morphological in nature, with identifiable alterations in the appearance of the vasculature or of the retina.
The identification of a limited set of retinal problems is made possible by analyses of images of the fundus, using one or more of the many fundus imaging modalities such as scanning laser ophthalmoscopy (or a confocal version thereof), or by optical coherence tomography (OCT; see for example, Huang et al. 1991), which can provide three-dimensional structural information, especially that of the retina.
An important anatomical region of the eye is that of the macula, depicted in the 2D image of FIG. 1a. Macular subregions have their own identifications, such as the fovea, foveal avascular zone (FAZ), the foveal pit, and the foveola. Many pathologies of the eye are identified by analysis of optical images of this region.
Retinal layers, depicted in the OCT image of FIG. 1b, normally consist of the retinal nerve fiber layer (RNFL or NFL), the ganglion cell layer (GCL), the inner plexiform layer (IPL), the inner nuclear layer (INL) containing the somae (cell bodies) of the bipolar, amacrine, horizontal, and Mueller cells, the outer plexiform layer (OPL), the outer nuclear layer (ONL) containing the somae of the photoreceptors, and the outer segments (OS) and inner segments (IS) of the photoreceptors. The external or outer limiting membrane (ELM or OLM) is the layer between the nuclei of the photoreceptors and their inner segments. The outer segments are embedded into the villi of the cells forming the retinal pigment epithelium (RPE) which itself is attached to the basement membrane.
Alternatively, functional imaging can reveal different aspects of retinal diseases, especially in the case of DR. Functional information, traditionally blood flow, may be derived using a variety of techniques such as the invasive fluorescein angiography (using injectable toxic dyes) and Doppler optical coherence tomography (D-OCT), which is limited in its applicability for functional imaging of the capillary network due to a near orthogonal Doppler angle.
A relatively new technique, using optical coherence tomography (OCT), is able to provide functional information by processing multiple images taken over time using intensity and/or phase fluctuations to highlight motion, such as blood flow within vessels. Thus functional information can be derived for flow in the retinal vasculature, as well as flow within the choroidal vasculature. And, OCT provides depth information, unlike the traditional angiography associated with a fundus imaging modality. These uses of OCT are collectively labelled as OCT Angiography (OCT-A) or functional OCT.
Foveal Avascular Zone (FAZ)
The anatomic macula is defined as that area of the posterior retina having at least two layers of nuclei in the ganglion cell layer. Clinically, this area extends 6 to 7 mm from the temporal edge of the optic nerve. FIG. 1b depicts an OCT scan of retina including the fovea (indicated by 101 in FIG. 1b) obtained with an optical coherence tomographic system (OCT).
A typical anatomic fovea is 1.5 mm in diameter and centered 4 mm temporal and 0.5 mm inferior to the center of the optic nerve head. The inner retinal surface of the fovea is typically concave in a healthy eye. There are typically no blood vessels in the central fovea in a healthy eye. This capillary-free zone in the fovea is 400 to 500 μm in diameter, and is called the foveal avascular zone (FAZ).
The center of the fovea is the foveola or foveal pit. It is roughly 350 μm in diameter and is contained within the foveal avascular zone. At this center, it is free of cells except for red and green cone photoreceptors. In the portion of the fovea surrounding the foveola, these layers: RNFL, GCL+IPL, and INL, are not present (although in shallow foveal pits, the INL may be continuous underneath the foveola). The disappearance of these layers at the foveal boundary can be seen in FIG. 1b. The layers of the ONL and below are the only ones present in this particular fovea.
The FAZ has been extensively studied in the past (see for example, Bresnick et al. 1984; Arend et al. 1995/1997; Sakata et al. 2006/2007; Chui et al. 2014; Tyrberg et al. 2008; Otani et al. 2007; Kim et al. 2012; Bolz et al. 2009; Springer & Hendrickson 2004a/2004b/2005; Tick et al. 2011; Dubis et al. 2009; Dmuchowska et al. 2012; and references cited within all of these citations). When DR is present, the FAZ area may be enlarged due to a disturbed macular circulation (i.e., a functional characteristic). These changes have been shown to be clinically significant in association with the progression of the disease and to result in macular ischemia (with the concomitant loss of visual function and acuity), disturbed electroretinograms, decreased contrast sensitivity, and visual field defects. There have been reports demonstrating an altered vascular function shown by a fluorescein angiographic image and neuroglial pathomorphology as depicted by OCT. Previous studies have shown reduced capillary blood flow, decreased capillary density in diabetic patients and also have demonstrated that progressive capillary loss in the FAZ was related to decreased visual acuity in these patients.
PED: Retinal Pigment Epithelium Detachment
Detachment of the retinal pigment epithelium is characteristic of a variety of chorio-retinal diseases including age-related macular degeneration (see for example Zayit-Soudry et al. 2007). Various types of pigment epithelial detachments (PEDs) have been identified including serous, fibrovascular, and drusenoid among others (see, e.g., Hartnett et al. 1992). Optical coherence tomography (OCT) has provided a way to visualize, segment, and classify PEDs (see for example, Stetson et al. 2013).
AMD: Age-related Macular Degeneration
Age related macular degeneration (AMD) results in the loss of visual acuity typically resulting from progressive degeneration of the choriocapillaris, the RPE, and photoreceptors. However, the earliest manifestation of the disease is likely to be a disruption of the basement membrane (see for example, Hageman 2015). Progressed levels of the disease are identifiable by the submacular neovascularization, geographic atrophy (normally related to a complete loss of the RPE, potentially together with loss of the chorio-capillaris, and photoreceptors). The disease normally begins in the dry form and may progress to geographic atrophy or a ‘wet’ or neovascularized version. In the presence of neovascularization, there is an accumulation of fluid, hemorrhage, and lipid exudation within the macula that can result in fibrosis, which is referred to as a disciform scar.
Exudates
Exudates are accumulations of lipids or lipid residues that have leaked from damaged capillaries. The most prevalent cause is from diabetes. Other causes can be retinal vein occlusion, hypertensive retinopathy, angiomas (von Hippel-Lindau disease), other vascular dysplasias, and radiation-induced vasculopathy.